1,8-Annelated quinoline derivatives substituted with carbon-linked triazoles as farnesyl transferase inhibitors

ABSTRACT

This invention comprises the novel compounds of formula (I)  
                 
 
wherein r, s, A, X, Y 1 , Y 2 , R 1 , R 2 , R 3 , and R 4  have defined meanings, having farnesyl transferase inhibiting activity; their preparation, compositions containing them and their use as a medicine.

The present invention is concerned with novel 1,8-annelated quinolinederivatives substituted with carbon-linked triazoles, the preparationthereof, pharmaceutical compositions comprising said novel compounds andthe use of these compounds as a medicine as well as methods of treatmentby administering said compounds.

Oncogenes frequently encode protein components of signal transductionpathways, which lead to stimulation of cell growth and mitogenesis.Oncogene expression in cultured cells leads to cellular transformation,characterized by the ability of cells to grow in soft agar and thegrowth of cells as dense foci lacking the contact inhibition exhibitedby non-transformed cells. Mutation and/or overexpression of certainoncogenes are frequently associated with human cancer. A particulargroup of oncogenes is known as ras, which have been identified inmammals, birds, insects, mollusks, plants, fungi and yeasts. The familyof mammalian ras oncogenes consists of three major members (“isoforms”):H-ras, K-ras and N-ras oncogenes. These ras oncogenes code for highlyrelated proteins generically known as p21^(ras). Once attached to plasmamembranes, the mutant or oncogenic forms of p21^(ras) will provide asignal for the transformation and uncontrolled growth of malignanttumour cells. To acquire this transforming potential, the precursor ofthe p21^(ras) oncoprotein must undergo an enzymatically catalyzedfarnesylation of the cysteine residue located in a carboxyl-terminaltetrapeptide. Therefore, inhibitors of the enzymes that catalyse thismodification, i.e. farnesyl transferase, will prevent the membraneattachment of p21^(ras) and block the aberrant growth of ras-transformedtumours. Hence, it is generally accepted in the art that farnesyltransferase inhibitors can be very useful as anticancer agents fortumours in which ras contributes to transformation.

Since mutated oncogenic forms of ras are frequently found in many humancancers, most notably in more than 50% of colon and pancreaticcarcinomas (Kohl et al., Science, vol 260, 1834-1837, 1993), it has beensuggested that farnesyl tranferase inhibitors can be very useful againstthese types of cancer.

In EP-0,371,564 there are described (1H-azol-1-ylmethyl) substitutedquinoline and quinolinone derivatives, which suppress the plasmaelimination of retinoic acids. Some of these compounds also have theability to inhibit the formation of androgens from progestines and/orinhibit the action of the aromatase enzyme complex.

In WO 97/16443, WO 97/21701, WO 98/40383 and WO 98/49157, there aredescribed 2-quinolinone derivatives, which exhibit farnesyl transferaseinhibiting activity. WO 00/39082 describes a class of novel1,2-annelated quinoline compounds, bearing a nitrogen- or carbon-linkedimidazole, which show farnesyl protein transferase and geranylgeranyltransferase inhibiting activity. Other quinolinone compounds havingfarnesyl transferase inhibiting activity are described in WO 00/12498,00/12499, 00/47574 and 01/53289.

Unexpectedly, it has been found that the present novel compounds, allhaving a phenyl substituent on the 4-position of the 1,8-annelatedquinolinone moiety bearing a carbon-linked triazole, show farnesylprotein transferase inhibiting activity. The present compounds may haveadvantage properties with regard to solubility and stability.

The present invention concerns compounds of formula (I):

-   -   or a pharmaceutically acceptable salt or N-oxide or        stereochemically isomeric form thereof, wherein    -   r and s are each independently 1, 2 or 3;    -   X is oxygen or sulfur;    -   -A- is a bivalent radical of formula        —CH═CH—  (a-1)        —CH₂—CH₂—  (a-2)        —CH₂—CH₂—CH₂—  (a-3)        —CH₂—O—  (a-4) or        —CH₂—CH₂—O—  (a-5)        -   wherein optionally one hydrogen atom may be replaced by            C₁₋₄alkyl;    -   >Y¹—Y²— is a trivalent radical of formula        >C═CR⁵—  (y-1) or        >CH—CHR⁵—  (y-2),        -   wherein R⁵ is hydrogen, halo or C₁₋₆alkyl;    -   R¹ is hydrogen, hydroxy, halo, cyano, nitro, C₁₋₆alkyl,        —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl, cyanoC₁₋₆alkyl,        hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, trihalomethyl,        -C₁₋₆alkyl-NR¹⁴R¹⁵, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy,        trihalomethoxy, C₂₋₆alkenyl, C₂₋₆alkynyl, —CHO,        C₁₋₆alkylcarbonyl, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,        —CONR¹⁴R¹⁵, —CONR¹⁴—O—C₁₋₆alkyl, —CONR¹⁴-C₁₋₆alkenyl, —OC(O)R¹⁶,        —CR¹⁶═NR¹⁷ or —CR¹⁶═N—OR¹⁷;        -   p is 0, or 2;        -   R¹² and R¹³ are independently hydrogen or C₁₋₆ alkyl and are            independently defined for each iteration of p in excess of            1;        -   R¹⁴ and R¹⁵ are independently hydrogen, C₁₋₆ alkyl or            —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl;    -   two R¹ substituents adjacent to one another on the phenyl ring        may form together a bivalent radical of formula        —O—CH₂—O—  (b-1)        —O—CH₂—CH₂—O—  (b-2)        —O—CH═CH—  (b-3) or        —O—CH₂—CH₂—  (b-4);        -   R¹⁶ and R¹⁷are independently hydrogen, C₁₋₆ alkyl or            —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl;    -   R² is hydrogen, hydroxy, halo, cyano, nitro, C₁₋₆alkyl,        C₁₋₆alkyloxy, trihalomethyl, C₁₋₆alkylthio, di(C₁₋₆alkyl)amino,        -C₁₋₆alkyl-NR¹⁴R¹⁵, trihalomethoxy, C₂₋₆alkenyl,        hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR¹⁴R¹⁵,        —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl, cyanoC₁₋₆alkyl, mono- or        di-haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,        R¹⁶SC₁₋₆alkyl, Het¹C₁₋₆alkyl, Het¹C₁₋₆alkyl in which the        C₁₋₆alkyl moiety is substituted by hydroxy, Het¹SC₁₋₆ alkyl,        -   -C₁₋₆alkylNR¹⁴-C₁₋₆alkyloxyC₁₋₆alkyl, -C₁₋₆            alkylNR¹⁴C₂₋₆alkenyl, -C₁₋₆alkylNR¹⁴C₂₋₆alkynyl,            -C₁₋₆alkylNR¹⁴C₁₋₁₆alkyl-NR¹⁴R¹⁵,            -C₁₋₆alkylNR¹⁴C₁₋₆alkyl-Het¹,            -C₁₋₆alkylNR¹⁴C₁₋₆alkylC(O)OC₁₋₆alkyl, C₂₋₆alkynyl, —CHO,            C₁₋₆alkylcarbonyl, —CONR¹⁴-C₁₋₆alkyl-NR¹⁴R¹⁵,            —CONR¹⁴—O-C₁₋₆alkyl, —CONR¹⁴-C₁₋₆alkenyl, —NR¹⁴R¹⁵,            —OC(O)R¹⁶, —CR¹⁶═NR¹⁷, —CR¹⁶═N—OR or —C(NR¹⁸R¹⁹)═NR²⁰;    -   two R² substituents adjacent to one another on the phenyl ring        may together form a bivalent radical of formula        —O—CH₂—O—  (b-1),        —O—CH₂—CH₂—O—  (b-2)        —O—CH═CH—  (b-3)        —O—CH₂—CH₂—  (b-4) or        —CH₂—O—CH₂  (b-5);        -   R¹⁶ and R¹⁷ are independently hydrogen, C₁₋₆ alkyl or            —(CR¹²R¹³)_(p)-C₃₋₁₀ocycloalkyl;        -   R¹⁸, R¹⁹ and R²⁰ are independently hydrogen and C₁₋₆alkyl;    -   R³ is hydrogen, halo, C₁₋₆alkyl, —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl,        haloC₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl,        C₁₋₆alkyloxyC₁₋₆alkyl, hydroxycarbonylC₁₋₆alkyl,        C₁₋₆alkyloxycarbonylC₁₋₆alkyl, -C₁₋₆alkyl-NR¹⁴R¹⁵,        -C₁₋₆alkyl-CONR¹⁴R¹⁵, Het¹, or a radical of formula        —O—R⁶  (c-1)        —NR⁷R⁸  (c-2) or        —N═CR⁶R⁷  (c-3)        -   wherein R⁶ is hydrogen, C₁₋₆alkyl,            —(CR¹²R¹³)_(p)-C₃₋₁₀ocycloalkyl, a group of formula —NR¹⁴R¹⁵            or -C₁₋₆alkylC(O)OC₁₋₆alkyl NR¹⁴R¹⁵, or a radical of formula            -Alk-OR⁹ or -Alk-NR¹⁰R¹¹;        -   R⁷ is hydrogen, C₁₋₆alkyl, —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl;        -   R⁸ is hydrogen, hydroxy, C₁₋₆alkyl,            —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl, C₁₋₆alkylcarbonylamino,            C₁₋₆alkylcarbonyl, haloC₁₋₆alkylcarbonyl,            Ar¹C₁₋₆alkylcarbonyl, Het¹C₁₋₆alkylcarbonyl, Ar¹carbonyl,            C₁₋₆alkyloxycarbonyl, trihaloC₁₋₆alkyloxycarbonyl,            C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, aminocarbonyl, mono- or            di(C₁₋₆alkyl)aminocarbonyl wherein the alkyl moiety may            optionally be substituted by one or more substituents            independently selected from Ar¹ and C₁₋₆alkyloxycarbonyl            substituents; aminocarbonylcarbonyl, mono- or            di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, or a radical of formula            -Alk-OR⁹ or Alk-NR¹⁰R¹¹; wherein Alk is C₁₋₆alkanediyl;        -   R⁹ is hydrogen, C₁₋₆alkyl, —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl;        -   R¹⁰ is hydrogen, C₁₋₆alkyl, —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl;        -   R¹¹ is hydrogen, C₁₋₆alkyl, —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl;        -   R⁴ is hydrogen or C₁₋₆alkyl;        -   Ar¹ is phenyl, naphthyl or phenyl, or naphthyl substituted            by one to five substituents each independently selected from            halo, hydroxy, cyano, nitro, amino, C₁₋₆alkyl,            haloC₁₋₆alkyl, -alkylNR¹⁴R¹⁵, C₁₋₆alkyloxy, OCF₃,            hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, aryloxy, —NR¹⁴R¹⁵,            C₁₋₆alkylsulfonylamino, oxime or phenyl, or a bivalent            substituent of formula —O—CH₂—O— or —O—CH₂—CH₂—O—;        -   Het¹ is a mono- or bi-cyclic heterocyclic ring containing            one or more heteroatoms selected from oxygen, sulphur and            nitrogen and optionally substituted by one or two            substituents each independently selected from halo, hydroxy,            cyano, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, -alkylNR¹⁴R¹⁵,            C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,            —CONR¹⁴R¹⁵, —NR¹⁴R¹⁵, C₁₋₆alkylsulfonylamino, oxime or            phenyl.        -   aryl is phenyl, naphthalenyl, phenyl substituted with one or            more substituents each independently selected from halo,            C₁₋₆alkyl, C₁₋₆alkyloxy, trifluoromethyl, cyano, or            hydroxycarbonyl; or naphtalenyl substituted with one or more            substituents each independently selected from halo,            C₁₋₆alkyl, C₁₋₆alkyloxy, trifluoromethyl, cyano or            hydroxycarbonyl;

As used in the foregoing definitions and hereinafter, halo is generic tofluoro, chloro, bromo and iodo; C₁₋₂alkyl defines methyl and ethyl;C₁₋₄alkyl includes C₁₋₂alkyl and straight and branched chain saturatedhydrocarbon radicals having from 3 to 4 carbon atoms such as, e.g.propyl, butyl, 1-methylethyl, 2-methylpropyl and the like; C₁₋₆alkylincludes C₁₋₄alkyl and the higher homologues thereof having 5 to 6carbon atoms such as, for example, pentyl, 2-methyl-butyl, hexyl,2-methylpentyl and the like; C₁₋₆alkanediyl defines bivalent straightand branched chained saturated hydrocarbon radicals having from 1 to 6carbon atoms, such as, for example, methylene, 1,2-ethanediyl,1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and thebranched isomers thereof; haloC₁₋₆alkyl defines C₁₋₆alkyl containing oneor more halo substituents for example trifluoromethyl; C₂₋₆alkenyldefines straight and branched chain hydrocarbon radicals containing onedouble bond and having from 2 to 6 carbon atoms such as, for example,ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl,3-methyl-2-butenyl, and the like.

The pharmaceutically acceptable salts as mentioned hereinabove are meantto comprise the therapeutically active non-toxic acid and base additionsalt forms, which the compounds of formula (I) are able to form. Thecompounds of formula (I) which have basic properties can be converted intheir pharmaceutically acceptable acid addition salts by treating saidbase form with an appropriate acid. Appropriate acids comprise, forexample, inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid; sulfuric; nitric; phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid),maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-amino-salicylic, pamoic and the like acids.

The compounds of formula (I) which have acidic properties may beconverted in their pharmaceutically acceptable base addition salts bytreating said acid form with a suitable organic or inorganic base.Appropriate base salt forms comprise, for example, the ammonium salts,the alkali and earth alkaline metal salts, e.g. the lithium, sodium,potassium, magnesium, calcium salts and the like, salts with organicbases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, andsalts with amino acids such as, for example, arginine, lysine and thelike.

The term “acid or base addition salts” also comprises the hydrates andthe solvent addition forms, which the compounds of formula (I) are ableto form. Examples of such forms are e.g. hydrates, alcoholates and thelike.

Compounds of formula (I) can be in the zwitterion form.

The term stereochemically isomeric forms of compounds of formula (I), asused hereinbefore, defines all possible compounds made up of the sameatoms bonded by the same sequence of bonds but having differentthree-dimensional structures which are not interchangeable, which thecompounds of formula (I) may possess. Unless otherwise mentioned orindicated, the chemical designation of a compound encompasses themixture of all possible stereochemically isomeric forms, which saidcompound might possess. Said mixture may contain all diastereomersand/or enantiomers of the basic molecular structure of said compound.All stereochemically isomeric forms of the compounds of formula (I) bothin pure form or in admixture with each other are intended to be embracedwithin the scope of the present invention.

Some of the compounds of formula (I) may also exist in their tautomericforms. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

Wherever -A- is a bivalent radical of formula (a-4) or (a-5), the CH2moiety in said bivalent radical is preferably connected to the nitrogenatom of the 2-quinolinone-moiety of the compounds of formula (I) or theintermediates of formula (II).

Whenever used hereinafter, the term “N-imidazolyl” means that theimidazolyl is attached to the rest of the molecule through a nitrogenatom.

Whenever used hereinafter, the term “compounds of formula (I)” is meantto include also the pharmaceutically acceptable acid and base additionsalts and all stereoisomeric forms.

A group of interesting compounds consists of those compounds of formula(I) wherein one or more of the following restrictions apply;

-   -   a) r and s are each independently 1    -   b) X is oxygen;    -   c) -A- is a bivalent radical of formula (a-2) or (a-3);    -   d) >Y¹—Y²— is a trivalent radical of formula (y-1) wherein R⁵ is        hydrogen;    -   e) R¹ is halo, C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl;    -   f) R² is halo, cyano, nitro, C₁₋₆alkyl, cyanoC₁₋₆alkyl,        hydroxyC₁₋₆alkyl or Het¹C₁₋₆alkyl;    -   g) R³ is hydrogen, cyanoC₁₋₆alkyl, -C₁₋₆alkyl-CONH₂, Het¹ or is        a radical of (c-1), (c-2), or (c-3) wherein R⁶ is hydrogen, R⁷        is hydrogen or C₁₋₆alkyl and R⁸ is hydrogen, hydroxy or        C₁₋₆alkyl;    -   h) R⁴ is C₁₋₂alkyl.

Another group of interesting compounds consists of those compounds offormula (I) wherein one or more of the following restrictions apply;

-   -   a) r and s are each independently 1;    -   b) X is oxygen;    -   c) -A- is a bivalent radical of formula (a-2) or (a-3);    -   d) >Y¹—Y²— is a trivalent radical of formula (y-1) wherein R⁵ is        hydrogen;    -   e) R² is halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl or        C₁₋₆alkyloxy;    -   f) R² is halo, cyano, C₁₋₆alkyl, cyanoC₁₋₁₆alkyl,        hydroxyC₁₋₆alkyl or Het¹C₁₋₆alkyl;    -   g) R³ is hydrogen, cyanoC₁₋₆alkyl, -C₁₋₆alkyl-CONH₂, Het¹ or is        a radical of (c-1), (c-2), or (c-3) wherein R⁶ is hydrogen, R⁷        is hydrogen or C₁₋₆alkyl and R⁸ is hydrogen, hydroxy or        C₁₋₆alkyl;    -   h) R⁴ is C₁₋₂alkyl.

A further group of interesting compounds consists of those compounds offormula (I) wherein one or more of the following restrictions apply;

-   -   a) r and s are each independently 1;    -   b) X is oxygen;    -   c) -A- is a bivalent radical of formula (a-2), (a-3) or (a-4);    -   d) >Y¹—Y²— is a trivalent radical of formula (y-1) wherein R⁵ is        hydrogen or halo;    -   e) R¹ is halo;    -   f) R² is halo or cyano;    -   g) R³is hydrogen, hydroxy, amino, C₁₋₆alkyloxy,        hydroxyC₁₋₆alkyloxy, C₁₋₆alkylcarbonylamino or N-imidazolyl;    -   h) R⁴ is C₁₋₂alkyl.

A more interesting group of compounds consists of those compounds offormula (I) wherein one or more of the following restrictions apply;

-   -   a) R¹ is 3-chloro, 3-bromo, 3-methyl, or 3-ethyloxy;    -   b) R² is in the para-position, or 1N-1,2, 3, 4        tetrazolylC₁₋₆alkyl;    -   c) R³ is NH₂ or N-imidazolyl;    -   d) R⁴is methyl.

A particular group of compounds consists of those compounds of formula(I) wherein r and s are each independently 1; X is oxygen; -A- is abivalent radical of formula (a-2); >Y¹Y²- is a trivalent radical offorrnula (y-1) wherein R⁵ is hydrogen; R¹ is halo or C₁₋₆alkyl; R² ishalo, cyano, C₁₋₆alkyl or Het¹C₁₋₆alkyl; R³is hydrogen, hydroxy, NH₂ orHet¹; and R⁴ is C₁₋₂alkyl.

A further particular group of compounds consists of those compounds offormula (I) wherein r and s are each independently 1; X is oxygen; -A-is a bivalent radical of formula (a-2); >Y¹—Y²— is a trivalent radicalof formula (y-1) wherein R⁵ is hydrogen; R¹ is halo, C₁₋₆alkyl, orC₁₋₆alkyloxy; R² is halo, cyano, C₁₋₆alkyl or Het¹C₁₋₆alkyl; R³ ishydrogen, hydroxy, NH₂ or Het¹; and R⁴is C₁₋₂alkyl.

Preferred compounds are those compounds of formula (I) wherein r and sare each independently 1; X is oxygen; -A- is a bivalent radical offormula (a-2), (a-3) or (a-4); >Y¹—Y²— is a trivalent radical of formula(y-1) wherein R⁵is hydrogen or halo; R¹ is halo; R² is halo or cyano;R³is hydrogen, hydroxy, amino, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy,C₁₋₆alkylcarbonylamino or N-imidazolyl; and R⁴ is C₁₋₂alkyl.

Most preferred compounds are

-   -   6-(3-chlorophenyl)-1,2-dihydro-8-[(4-iodophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-4H-pyrrolo[3,2,1-ij]quinolin-4-one;    -   4-[[6-(3-chlorophenyl)-1,2-dihydro-4-oxo-4H-pyrrolo[3,2,1-ij]quinolin-8-yl](4-methyl-4H-1,2,4-triazol-3-yl)methyl]-        benzonitrile;    -   7-(3-chlorophenyl)-9-[(4-chlorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-2,3-dihydro-1H,5H-benzo[ij]quinolizin-5-one;    -   6-(3-chlorophenyl)-8-[(4-fluorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one;    -   6-(4-chlorophenyl)-8-[(4-chlorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one;    -   6-(3-bromophenyl)-8-[(4-bromophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one;    -   N-[[6-(3-chlorophenyl)-1,2-dihydro-4-oxo-4H-pyrrolo[3,2,1-ij]quinolin-8-yl](4-fluorophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-acetamide;    -   7-(3-chlorophenyl)-9-[(4-chlorophenyl)methoxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-2,3-dihydro-1H,5H-benzo[ij]quinolizin-5-one;    -   6-(3-chlorophenyl)-8-[(4-fluorophenyl)(2-hydroxyethoxy)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one;    -   6-(3-chlorophenyl)-8-[(4-fluorophenyl)- I        H-imidazol-1-yl(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one;    -   8-[amino(4-fluorophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-6-(3-chlorophenyl)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one        and their pharmaceutically acceptable salts.

The compounds of formula (I) and their pharmaceutically acceptable saltsand N-oxides and stereochemically isomeric forms thereof may beprepared, for example, by the following processes:

-   -   a) Compounds of formula (I), wherein R⁴ is C₁₋₆alkyl and R³ is        hydroxy, said compounds being referred to as compounds of        formula (I-a), may be prepared by reacting an intermediate        ketone of formula (II) with an intermediate triazole reagent of        formula (III-a) wherein R²¹ is hydrogen or C₁₋₆ alkyl, to form        intermediates of formula (IVa) and subsequently removing the        3-mercapto or the 3-C₁₋₆alkylmercapto group. More in particular,        the compounds of formula (I-a) may be prepared by reacting the        compound of formula (II) with the triazole reagent (III-a),        preferably in a reaction-inert solvent such as tetrahydrofuran,        in the presence of a strong base such as butyl lithium at a        temperature ranging from −78° C. to room temperature. Removal of        the 3-mercapto group is conveniently effected with sodium        nitrite, for example in THF/H₂O in the presence of nitric acid.        Removal of, for example, the 3-methylmercapto group is        conveniently effected with Raney Nickel in ethanol or acetone.        Another method for obtaining intermediates of formula (IVa)        starting from intermediates of formula (II) is described in the        examples.    -   b) Compounds of formula (I), wherein R⁴ is hydrogen and R³ is        hydroxy, said compounds being referred to as compounds of        formula (I-b), may be prepared by reacting an intermediate        ketone of formula (II) with an intermediate triazole reagent of        formula (III-b) wherein P is an optional protective group such        as, for example, a sulfonyl group, e.g. a dimethylamino sulfonyl        group, which can be removed after the addition reaction. Said        reaction requires the presence of a suitable strong base, such        as, for example, butyl lithium in an appropriate solvent such as        tetrahydrofuran

Compounds of formula (I-a) and (I-b) can optionally be the subject ofone or more of the following conversions in any desired order:

-   -   (i) converting a compound of formula (I) into a different        compound of formula (I);    -   (ii) converting a compound of formula (I) into a        pharmaceutically acceptable salt or N-oxide thereof;    -   (iii) converting a pharmaceutically acceptable salt or N-oxide        of a compound of formula (I) into the parent compound of formula        (I);    -   (iv) preparing a stereochemical isomeric form of a compound of        formula (I) or a pharmaceutically acceptable salt or N-oxide        thereof.

Examples of the conversion of one compound of formula (I) into adifferent compound of formula (I) include the following reactions:

-   -   a) Compounds of formula (I-c) wherein R³ is hydroxy, can be        converted into compounds of formula (I-d), defined as a compound        of formula (I) wherein R³ is hydrogen, by submitting the        compounds of formula (I-c) to appropriate reducing conditions,        such as, e.g. stirring in acetic acid in the presence of        formamide, or treatment with sodium borohydride/ trifluoroacetic        acid.    -   b) Compounds of formula (I-c) can be converted to compounds of        formula (I-e) wherein R³ is halo, by reacting the compounds of        formula (I-c) with a suitable halogenating agent, such as, e.g.        thionyl chloride or phosphorus tribromide. Successively, the        compounds of formula (I-e) can be treated with a reagent of        formula H-NR⁷R⁸ in a reaction-inert solvent, thereby yielding        compounds of formula (I-f).    -   c) Compounds of formula (I-c) can be converted into compounds of        formula (I-f), for example, by treatment with SOCl2, and then        NH₃/iPrOH, e.g. in a tetrahydrofuran solvent, or by treatment        with acetic acid ammonium salt at a temperature ranging from 120        to 180° C., or by treatment with sulfamide at a temperature        ranging from 120 to 180° C.    -   d) A compound of formula (I-h), defined as a compound of        formula (I) wherein X is sulfur, may be prepared by reacting the        corresponding compound of formula (I-g), defined as a compound        of formula (I) wherein X is oxygen, with a reagent like        phosphorus pentasulfide or Lawesson's reagent in a suitable        solvent such as, for example, pyridine.    -   e) Compounds of formula (I) in which >Y¹—Y² represents a radical        of formula (y-1) can be converted into corresponding compounds        of formula (I) in which >Y¹—Y² represents a radical of formula        (y-2) by conventional reduction procedures, for example,        hydrogenation or reduction by treatment with sodium borohydride        in a suitable solvent, e.g. methanol and vice versa by        conventional oxidation procedures such as, for example,        treatment with bromine in an appropriate solvent such as, e.g.        bromobenzene, or treatment with iodine in the presence of acetic        acid and potassium acetate. Said oxidation reaction can give        rise to side-products wherein the bivalent radical -A- is        oxidized. For instance, oxidation of intermediates of        formula (II) in which >Y¹—Y² represents a radical of formula        (y-2), wherein -A- is (a-2) may give intermediates of        formula (II) in which >Y¹—Y² represents a radical of formula        (y-1) wherein -A- is (a-1).

f) The compounds of formula (I) may also be converted into each othervia art-known reactions or functional group transformations. A number ofsuch transformations are already described hereinabove. Other examplesare hydrolysis of carboxylic esters to the corresponding carboxylic acidor alcohol; hydrolysis of amides to the corresponding carboxylic acidsor amines; hydrolysis of nitriles to the corresponding amides; aminogroups on imidazole or phenyl may be replaced by a hydrogen by art-knowndiazotation reactions and subsequent replacement of the diazo-group byhydrogen; alcohols may be converted into esters and ethers; primaryamines may be converted into secondary or tertiary amines; double bondsmay be hydrogenated to the corresponding single bond; an iodo radical ona phenyl group may be converted in to an ester group by carbon monoxideinsertion in the presence of a suitable palladium catalyst.

The intermediates and starting materials used in the above-describedprocesses may be prepared in conventional manner using procedures knownin the art for example as described in the above-mentioned patentspecifications WO 97/16443, WO 97/21701, WO 98/40383, WO 98/49157 and WO00/39082.

For example intermediates of formula (II) can be prepared by proceduresdescribed in International Patent Specification No. WO 98/40383, frompage 11 to page 13, or by processes analogous thereto. In addition anintermediate keton of formula (II) can be prepared by reacting anintermediate compound of formula (V) with an intermediate compound offormula (VI) wherein Z represents B(OH)₂ or Sn(C₁₋₄alkyl)₃, and additionof carbon monoxide at atmospheric pressure or at an increased pressure,in the presence of a suitable palladium-catalyst (e.g. palladium oncharcoal), an appropriate base such as triethylamine and a suitablesolvent such as dioxane.

-   -   a) Intermediate ketons of formula (II) can also be prepared by        reacting intermediate compounds of formula (VII) with        intermediate compounds of formula (VIII) in the presence of a        suitable solvent such as tetrahydrofuran.    -   b) The intermediate compounds of formula (VII) can be prepared        by reacting intermediate compounds of formula (V) with        intermediate compounds of formula (IX) and addition of carbon        monoxide at atmospheric pressure or at an increased pressure, in        the presence of a suitable palladium-catalyst (e.g. palladium on        charcoal), an appropriate base such as triethylamine and a        suitable solvent such as dioxane.    -   c) The intermediate compounds of formula (V-a) wherein >Y¹—Y²—        is a trivalent radical of formula (y-2) wherein R⁵ is hydrogen        can be converted in intermediate compounds of formula (V-b)        wherein >Y¹—Y²²— is a trivalent radical of formula (y-1) wherein        R⁵ is hydrogen, in the presence of iodium, potassium acetate and        a suitable solvent such as acetic acid.    -   d) Intermediate compounds of formula (V-a) wherein X is oxygen,        can be prepared by reacting intermediate compounds of        formula (XI) with polyphosphoric acid (PPA).    -   e) Intermediate compounds of formula (XI) can be prepared by        reacting intermediate compounds of formula (XII) with        intermediate compounds of formula (XIII) in the presence of an        appropriate base such as triethylamine and a suitable solvent        such as dichloromethane (DCM).

The compounds of formula (I) and some of the intermediates have at leastone stereogenic centre in their structure. This stereogenic centre maybe present in an R or an S configuration.

The compounds of formula (I) as prepared in the hereinabove describedprocesses are generally racemic mixtures of enantiomers, which can beseparated from one another following art-known resolution procedures.The racemic compounds of formula (I) may be converted into thecorresponding diastereomeric salt forms by reaction with a suitablechiral acid. Said diastereomeric salt forms are subsequently separated,for example, by selective or fractional crystallization and theenantiomers are liberated therefrom by alkali. An alternative manner ofseparating the enantiomeric forms of the compounds of formula (I)involves liquid chromatography using a chiral stationary phase. Saidpure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound would be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

The compounds of formula (I), the pharmaceutically acceptable acidaddition salts and stereoisomeric forms thereof have valuablepharmacological properties in that they have a potent farnesyl proteintransferase (FPTase) inhibitory effect.

This invention provides a method for inhibiting the abnormal growth ofcells, including transformed cells, by administering an effective amountof a compound of the invention. Abnormal growth of cells refers to cellgrowth independent of normal regulatory mechanisms (e.g. loss of contactinhibition). This includes the abnormal growth of: (1) tumor cells(tumors) expressing an activated ras oncogene; (2) tumor cells in whichthe ras protein is activated as a result of oncogenic mutation ofanother gene; (3) benign and malignant cells of other proliferativediseases in which aberrant ras activation occurs. Furthermore, it hasbeen suggested in literature that ras oncogenes not only contribute tothe growth of tumors in vivo by a direct effect on tumor cell growth butalso indirectly, i.e. by facilitating tumor-induced angiogenesis (Rak.J. et al, Cancer Research, 55, 4575-4580, 1995). Hence,pharmacologically targeting mutant ras oncogenes could conceivablysuppress solid tumor growth in vivo, in part, by inhibitingtumor-induced angiogenesis.

This invention also provides a method for inhibiting tumour growth byadministering an effective amount of a compound of the presentinvention, to a subject, e.g. a mammal (and more particularly a human)in need of such treatment. In particular, this invention provides amethod for inhibiting the growth of tumours expressing an activated rasoncogene by the administration of an effective amount of the compoundsof the present invention. Examples of tumours which may be inhibited,but are not limited to, lung cancer (e.g. adenocarcinoma and includingnon-small cell lung cancer), pancreatic cancers (e.g. pancreaticcarcinoma such as, for example exocrine pancreatic carcinoma), coloncancers (e.g. colorectal carcinomas, such as, for example, colonadenocarcinoma and colon adenoma), prostate cancer including theadvanced disease, hematopoietic tumours of lymphoid lineage (e.g. acutelymphocytic leukemia, B-cell lymphoma, Burkitt's lymphoma), myeloidleukemias (for example, acute myelogenous leukemia (AML)), thyroidfollicular cancer, myelodysplastic syndrome (MDS), tumours ofmesenchymal origin (e.g. fibrosarcomas and rhabdomyosarcomas),melanomas, teratocarcinomas, neuroblastomas, gliomas, benign tumour ofthe skin (e.g. keratoacanthomas), breast carcinoma (e.g. advanced breastcancer), kidney carcinoma, ovary carcinoma, bladder carcinoma andepidermal carcinoma.

This invention may also provide a method for inhibiting proliferativediseases, both benign and malignant, wherein ras proteins are aberrantlyactivated as a result of oncogenic mutation in genes. With saidinhibition being accomplished by the administration of an effectiveamount of the compounds described herein, to a subject in need of such atreatment. For example, the benign proliferative disorderneuro-fibromatosis, or tumours in which ras is activated due to mutationor overexpression of tyrosine kinase oncogenes, may be inhibited by thecompounds of this invention.

The compound according to the invention can be used for othertherapeutic purposes, for example:

-   -   a) the sensitisation of tumours to radiotherapy by administering        the compound according to the invention before, during or after        irradiation of the tumour for treating cancer, for example as        described in WO 00/01411;    -   b) treating athropathies such as rheumatoid arthritis,        osteoarthritis, juvenile arthritis, gout, polyarthritis,        psoriatic arthritis, ankylosing spondylitis and systemic lupus        erythematosus, for example as described in WO 00/01386;    -   c) inhibiting smooth muscle cell proliferation including        vascular proliferative disorders, atherosclerosis and        restenosis, for example as described in WO 98/55124;    -   d) treating inflammatory conditions such as ulcerative colitis,        Crohn's disease, allergic rhinitis, graft vs host disease,        conjunctivitis, asthma, ARDS, Behcets disease, transplant        rejection, uticaria, allergic dermatitis, alopecia areata,        scleroderma, exanthem, eczema, dermatomyositis, acne, diabetes,        systemic lupus erythematosis, Kawasaki's disease, multiple        sclerosis, emphysema, cystic fibrosis and chronic bronchitis;    -   e) treating endometriosis, uterine fibroids, dysfunctional        uterine bleeding and endometrial hyperplasia;    -   f) treating ocular vascularisation including vasculopathy        affecting retinal and choroidal vessels;    -   g) treating pathologies resulting from heterotrimeric G protein        membrane fixation including diseases related to following        biological functions or disorders; smell, taste, light,        perception, neurotransmission, neurodegeneration, endocrine and        exocrine gland functioning, autocrine and paracrine regulation,        blood pressure, embryogenesis, viral infections, immunological        functions, diabetes, obesity;    -   h) inhibiting viral morphogenesis for example by inhibiting the        prenylation or the post-prenylation reactions of a viral protein        such as the large delta antigen of hepatitis D virus; and the        treatment of HIV infections;    -   i) treating polycystic kidney disease;    -   j) suppressing induction of inducible nitric oxide including        nitric oxide or cytokine mediated disorders, septic shock,        inhibiting apoptosis and inhibiting nitric oxide cytotoxicity;    -   k) treating malaria.

The compounds of present invention may be particularly useful for thetreatment of proliferative diseases, both benign and malignant, whereinthe K-ras B isoform is activated as a result of oncogenic mutation.

Hence, the present invention discloses the compounds of formula (I) foruse as a medicine as well as the use of these compounds of formula (I)for the manufacture of a medicament for treating one or more of theabove mentioned conditions.

For the treatment of the above conditions, the compound of the inventionmay be advantageously employed in combination with one or more othermedicinal agents such as anti-cancer agents for example selected fromplatinum coordination compounds for example cisplatin or carboplatin,taxane compounds for example paclitaxel or docetaxel, camptothecincompounds for example irinotecan or topotecan, anti-tumour vincaalkaloids for example vinblastine, vincristine or vinorelbine,anti-tumour nucleoside derivatives for example 5-fluorouracil,gemcitabine or capecitabine, nitrogen mustard or nitrosourea alkylatingagents for example cyclophosphamide, chlorambucil, carmustine orlomustine, anti-tumour anthracycline derivatives for exampledaunorubicin, doxorubicin or idarubicin; HER2 antibodies for exampletrastzumab; and anti-tumour podophyllotoxin derivatives for exampleetoposide or teniposide; and antiestrogen agents including estrogenreceptor antagonists or selective estrogen receptor modulatorspreferably tamoxifen, or alternatively toremifene, droloxifene, faslodexand raloxifene, or aromatase inhibitors such as exemestane, anastrozole,letrazole and vorozole.

For the treatment of cancer the compounds according to the presentinvention can be administered to a patient as described above, inconjunction with irradiation. Such treatment may be especiallybeneficial, as farnesyl transferase inhibitors can act asradiosensitisers, for example as described in International PatentSpecification WO 00/01411, enhancing the therapeutic effect of suchirradiation.

Irradiation means ionizing radiation and in particular gamma radiation,especially that emitted by linear accelerators or by radionuclides thatare in common use today. The irradiation of the tumour by radionuclidescan be external or internal.

Preferably, the administration of the farnesyl transferase inhibitorcommences up to one month, in particular up to 10 days or a week, beforethe irradiation of the tumour. Additionally, it is advantageous tofractionate the irradiation of the tumour and maintain theadministration of the farnesyl transferase inhibitor in the intervalbetween the first and the last irradiation session.

The amount of farnesyl protein transferase inhibitor, the dose ofirradiation and the intermittence of the irradiation doses will dependon a series of parameters such as the type of tumour, its location, thepatient's reaction to chemo- or radiotherapy and ultimately is for thephysician and radiologists to determine in each individual case.

The present invention also concerns a method of cancer therapy for ahost harboring a tumour comprising the steps of

-   -   administering a radiation-sensitizing effective amount of a        farnesyl protein transferase inhibitor according to the        invention before, during or after    -   administering radiation to said host in the proximity to the        tumour.

In view of their useful pharmacological properties, the subjectcompounds may be formulated into various pharmaceutical forms foradministration purposes.

To prepare the pharmaceutical compositions of this invention, aneffective amount of a particular compound, in base or acid addition saltform, as the active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs and solutions; orsolid carriers such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets.

Because of their ease in administration, tablets and capsules representthe most advantageous oral dosage unit form, in which case solidpharmaceutical carriers are obviously employed. For parenteralcompositions, the carrier will usually comprise sterile water, at leastin large part, though other ingredients, to aid solubility for example,may be included. Injectable solutions, for example, may be prepared inwhich the carrier comprises saline solution, glucose solution or amixture of saline and glucose solution. Injectable suspensions may alsobe prepared in which case appropriate liquid carriers, suspending agentsand the like may be employed. In the compositions suitable forpercutaneous administration, the carrier optionally comprises apenetration enhancing agent and/or a suitable wetting agent, optionallycombined with suitable additives of any nature in minor proportions,which additives do not cause a significant deleterious effect to theskin. Said additives may facilitate the administration to the skinand/or may be helpful for preparing the desired compositions. Thesecompositions may be administered in various ways, e.g., as a transdermalpatch, as a spot-on or as an ointment.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient, calculated to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

Those skilled in the art could easily determine the effective amountfrom the test results presented hereinafter. In general it iscontemplated that a therapeutically effective amount would be from 0.001mg/kg to 100 mg/kg body weight, and in particular from 0.1 mg/kg to 100mg/kg body weight. It may be appropriate to administer the required doseas two, three, four or more sub-doses at appropriate intervalsthroughout the day. Said sub-doses may be formulated as unit dosageforms, for example, containing 0.1 to 500 mg, and in particular 10 mg to500 mg of active ingredient per unit dosage form.

The following examples are provided for purposes of illustration.

Hereinafter “THF” means tetrahydrofuran, “DME” means1,2-dimethoxyethane, “EtOAc” means ethyl acetate, “eq” means equivalent,“DCM” means dichloromethane, “DMF” means dimethylformamide and “BuLi”means n-butyl lithium.

A. Preparation of the Intermediates

EXAMPLE A1

a) A mixture of(±)-6-(3-chlorophenyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(described in International Application WO98/40383) (0.211 mol) inpolyphosporic acid (600 g) was stirred at 140° C. overnight.4-lodo-benzoic acid (0.422 mol) was added portionwise. The mixture wasstirred at 140° C. overnight then brought to 100° C. and poured out intoice water. DCM was added. The precipitate was filtered over celite andwashed with DCM. The filtrate was extracted with DCM. The organic layerwas basified with K₂CO₃ (10%) then washed with water, dried (MgSO₄),filtered, and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (15-35 μm) (eluent: CH₂Cl₂/EtOAc;95/5). The pure fractions were collected and the solvent was evaporated,yielding 35 g (32%). A part of this fraction (1 g) was crystallized fromCH₃CN/2-propanone (warm). The precipitate was filtered off and driedunder a vacuo, yielding 0.77 g of6-(3-chlorophenyl)-1,2,5,6-tetrahydro-8-(4-iodobenzoyl)-4H-pyrrolo[3,2,1-ij]quinolin-4-one,melting point 275° C. (intermediate 1).

b) Acetic acid, potassium salt (0.22 mol) then iodine (0.147 mol) wereadded at room temperature to a solution of (intermediate 1) (0.061 mol)in acetic acid (300 ml). The mixture was stirred at 130° C. for 72hours, poured out into Na₂S₂O₃ 1 M/ice and extracted with DCM. Theorganic layer was washed with K₂CO₃ 10%, separated, dried (MgSO₄),filtered, and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (20-40 μm)(eluent:CH₂Cl₂/CH₃OH;95/5 to 60/40). Two fractions were collected and thesolvent was evaporated. Yielding: 4.0 g of starting material and 26.5 gF1 (84%). A part (0.7 g) of F1 was crystallized from 2-propanone. Theprecipitate was filtered off and dried, yielding 0.61 g of6-(3-chlorophenyl)-1,2-dihydro-8-(4-iodobenzoyl)-4H-pyrrolo[3,2,1-ij]quinolin-4-one,melting point 202° C. (intermediate 2).

c) A mixture of (intermediate 2) (0.0219 mol) and tosylmethyl isocyanide(0.0284 mol) was added at −5° C. to DME (330 ml) under N₂ flow. Ethanol(33 ml) then 2-methyl,2-propanol potassium salt (0.0525 mol) was addedportionwise at 5° C. The mixture was stirred at 10° C. for 1 hour and 30minutes, poured out into ice water and extracted with EtOAc. The organiclayer was separated, dried (MgSO₄), filtered, and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (15-35 μm) (eluent: toluene/EtOAc; 50/50). The pure fractionswere collected and the solvent was evaporated, yielding: 1.9 g of6-(3-chlorophenyl)-1,2-dihydro-α-(4-iodophenyl)-4-oxo-4H-pyrrolo[3,2,1-ij]quinoline-8-acetonitrile(intermediate 3).

d) A mixture of (intermediate 3) (0.0195 mol) in acetic acid (30 ml),sulfuric acid (30 ml) and water (30 ml) was stirred and refluxedovernight and poured out into ice water. The precipitate was filtered,washed with diethyl ether and dried under a vaccuo, yielding(quantitative)6-(3-chlorophenyl)-1,2-dihydro-α-(4-iodophenyl)-4-oxo-4H-pyrrolo[3,2,1-ij]quinoline-8-aceticacid (intermediate 4).

e) N′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine,monohydrochloride (0.021 mol), 1-hydroxybenzotriazole (0.021 mol) thenN-methyl-hydrazinecarbothioamide (0.021 mol) were added to a mixture of(intermediate 4) (0.017 mol) in THF (95 ml). The mixture was stirred atroom temperature for 48 hours and poured out into ice water. Theprecipitate was filtered off and dried, yielding 8.9 g (83%) of6-(3-chlorophenyl)-1,2-dihydro-α-(4-iodophenyl)-4-oxo-,2-[(methylamino)carbonothioyl]hydrazide4H-pyrrolo[3,2,1-ij]quinoline-8-acetic acid (intermediate 5). Theproduct was used without further purification in the next reaction step.

f) CH₃ONa (30%) in methanol (0.0133 mol) was added to a mixture of(intermediate 5) (0.0133 mol) in methanol (110 ml). The mixture wasstirred and refluxed for 3 hours then cooled, poured out into ice waterand extracted with DCM. The organic layer was separated, dried (MgSO₄),filtered, and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (15-40 μm) (eluent:CH₂Cl₂/CH₃OH/NH₄OH; 95/5/0.1). The pure fractions were collected and thesolvent was evaporated, yielding 4.35 g (53.5%) of6-(3-chlorophenyl)-1,2-dihydro-8-[(4-iodophenyl)(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methyl]-4H-pyrrolo[3,2,1-ij]quinolin-4-one(intermediate 6).

EXAMPLE A2

n-BuLi (0.0166 mol) was added slowly at −78° C. to a solution of2,4-dihydro-4-methyl-3H-1,2,4-triazole-3-thione (0.0082 mol) in THF (50ml) under N₂ flow. The mixture was stirred at 0° C. for 1 hour, thencooled to −78° C.9-(4-chlorobenzoyl)-7-(3-chlorophenyl)-2,3-dihydro-1H,5H-benzo[ij]quinolizin-5-one(described in International Application WO98/40383 ) (0.0046 mol) wasadded portionwise. The mixture was stirred at room temperature for 4hours, poured out on ice and extracted with EtOAc. The organic layer wasseparated, dried (MgSO₄), filtered, and the solvent was evaporated. Theresidue (2.32 g) was purified by column chromatography over silica gel(15-40 μm) (eluent: CH₂Cl₂/CH₃OH/NH₄OH 98/2/0.1 to 96/4/0.1). The purefractions were collected and the solvent was evaporated. The residue (1g, 40%). was crystallized from acetonitril. The precipitate was filteredoff and dried, yielding 0.52 g (21%) of7-(3-chlorophenyl)-9-[(4-chlorophenyl)hydroxy(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methyl]-2,3-dihydro-1H,5H-benzo[ij]quinolizin-5-onehydrate (1:1), melting point 160° C. (intermediate 7).

EXAMPLE A3

a) Triethylamine (0.05 mol) was added to a mixture of5-bromo-2,3-dihydro-1H-indole (0.025 mol) in DCM (35 ml). A solution of3-(3-chlorophenyl)-2-propenoyl chloride (0.0365 mol) in DCM (20 ml) wasadded dropwise. The mixture was stirred at room temperature overnight.Water was added. The mixture was extracted with DCM. The organic layerwas separated, dried (MgSO₄), filtered, and the solvent was evaporated.The residue (11.34 g) was dissolved in DCM and crystallized from diethylether. The precipitate was filtered off and dried to give 3.17 g ofintermediate 8. The filtrate was evaporated. The residue was dissolvedin DCM and crystallized from diethyl ether. The precipitate was filteredoff and dried, yielding 2.17 g (59%) of5-bromo-1-[(2E)-3-(3-chlorophenyl)-1-oxo-2-propenyl]-2,3-dihydro-1H-indole(intermediate 8).

b) A mixture of intermediate 8 (0.012 mol) and polyphosporic acid (60 g)was stirred at 140° C. overnight, poured out into ice water and NH₄OHand extracted with DCM. The organic layer was separated, dried (MgSO₄),filtered, and the solvent was evaporated. The residue (5.09 g) waspurified by column chromatography over silica gel (20-45 μm) (eluent:cyclohexane/EtOAc 60/40). The pure fractions were collected and thesolvent was evaporated, yielding 1.7 g of8-bromo-6-(3-chlorophenyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(intermediate 9).

b) 12 (0.0112 mol) and potassium acetate (0.0169 mol) were added to asolution of intermediate 9 (0.0047 mol) in acetic acid (12 ml). Themixture was stirred at 140° C. for 2 days. After the first night, 12(0.584 g, 0.5 eq) and potassium acetate (0.345 g, 0.75 eq) were added.The mixture was poured out into ice water and NaHSO₃. The precipitatewas filtered. DCM was added to the filtrate. The mixture was extractedwith DCM. The organic layer was washed with H₂O/NH₄OH, dried (MgSO₄),filtered and the solvent was evaporated. The residue (2.4 g) waspurified by column chromatography over silica gel (35-70 μm)(eluent:CH₂Cl₂/CH₃OH 98/2). The pure fractions were collected and the solventwas evaporated, yielding 1.38 g (82%) of8-bromo-6-(3-chlorophenyl)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(intermediate 10).

d) A mixture of intermediate 10 (0.0025 mol), N-methoxy-methanamine,hydrochloride (0.0055 mol), Pd(PPh₃)₄ (0.00025 mol) and triethylamine(0.0124 mol) in dioxane (30 ml) was stirred at 100° C. for 3 days undera 5 bar pressure of CO and poured out into ice water. DCM was added. Themixture was filtered over celite and extracted with DCM. The organiclayer was separated, dried (MgSO₄), filtered, and the solvent wasevaporated. The residue (1.71 g) was purified by column chromatographyover silica gel (15-40 μm) (eluent: CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.1). Thepure fractions were collected and the solvent was evaporated. Theresidue (0.56 g) was crystallized from DCM/diethyl ether. Theprecipitate was filtered off and dried, yielding 0.159 g of6-(3-chlorophenyl)-1,2-dihydro-N-methoxy-N-methyl-4-oxo-4H-pyrrolo[3,2,1-ij]quinoline-8-carboxamide,melting point 162° C. (intermediate 11).

e) Phenyl-lithium (0.00065 mol) was added at −78° C. to a solution ofintermediate 11 (0.00054 mol) in THF (4 ml) under N₂ flow. The mixturewas stirred at −78° C. for 2 hours. Water and ice were added. Themixture was extracted with EtOAc. The organic layer was separated, dried(MgSO₄), filtered, and the solvent was evaporated. The residue (0.172 g)was purified by column chromatography over silica gel (10 μm) (eluent:DCM 100). The pure fractions were collected and the solvent wasevaporated, yielding 0.011 g (5%) of8-benzoyl-6-(3-chlorophenyl)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(intermediate 12).

EXAMPLE A4 An Alternative Way for the Preparation of Intermediate 12Starting from Intermediate 10

A mixture of intermediate 10 (0.00078 mol), phenyl-boronic acid (0.0011mol), Pd(PPh₃)₄ (0.078 mol) and triethylamine (0.0038 mol) in dioxane(30 ml) was stirred at 100° C. for 4 days under a 5 bar pressure of COand poured out into ice water. DCM was added. The mixture was filteredover celite. Celite was washed with DCM. The organic layer wasseparated, dried (MgSO₄), filtered, and the solvent was evaporated.

The residue (0.31 g) was purified by column chromatography over silicagel (10 μm) (eluent: DCM100). The pure fractions were collected and thesolvent was evaporated, yielding 0.075 g (25%) of8-benzoyl-6-(3-chlorophenyl)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(intermediate 12).

EXAMPLE A5

nBuLi 1.6M in hexane (0.0086 mol) was added at −78° C. to a solution of2,4-dihydro-4-methyl-3H-1,2,4-triazole-3-thione (0.0043 mol) in THF (25ml) under N₂ flow. The mixture was stirred at 0° C. for 1 hour, thencooled to −78° C.8-(4-chlorobenzoyl)-6-(3-chlorophenyl)-2H,4H-oxazolo[5,4,3-ij]quinolin-4-one(0.0024 mol) described in International Publication WO98/40383, wasadded portionwise. The mixture was stirred at room temperature for 4hours, poured out into ice water and extracted with EtOAc. The organiclayer was separated, dried (MgSO₄), filtered, and the solvent wasevaporated. The residue (1.38 g) was purified by column chromatographyover silica gel (15-40 μm) (eluent: CH₂Cl₂/CH₃OH/NH₄OH97/3/0.1). Thepure fractions were collected and the solvent was evaporated. A part ofthe residue (0.049 g) was purified by column chromatography over silicagel (10 μm) (eluent: CH₂Cl₂/CH₃OH 98/2). The pure fractions werecollected and the solvent was evaporated, yielding 0.018 g (1%) of6-(3-chlorophenyl)-8-[(4-chlorophenyl)hydroxy(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methyl]-2H,4H-oxazolo[5,4,3-ij]quinolin-4-one,melting point: 193° C. (intermediate 13).

B. Preparation of the Final Compounds

EXAMPLE B1

Sodium nitrite (0.0057 mol) was added at 10° C. to a mixture of nitricacid (10.5 ml) and water (10.5 ml). A mixture of (intermediate 6)(0.0057 mol) in THF (35 ml) was added dropwise. The mixture was stirredat 10° C. for 1 hour, poured out into ice water, basified with K₂CO₃solid and extracted with EtOAc. The organic layer was separated, dried(MgSO₄), filtered, and the solvent was evaporated. The residue waspurified by column chromatography over silica gel (15-40 μm) (eluent:CH₂Cl₂/CH₃OH/NH₄OH; 94/6/0.1). The pure fractions were collected and thesolvent was evaporated, yielding 1.35 g (37.7%). A part of this fraction(0.55 g) was crystallized from CH₃CN/diethyl ether. The precipitate wasfiltered off and dried, yielding 0.35 g (10.5%) of6-(3-chlorophenyl)-1,2-dihydro-8-[(4-iodophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-4H-pyrrolo[3,2,1-ij]quinolin-4-one.hydrate (1:1), melting point 194° C. (compound I). Intermediate 13 canbe converted in a similar way into a similar endproduct.

EXAMPLE B2

N₂ was bubbled in a solution of6-(3-chlorophenyl)-1,2-dihydro-8-[(4-iodophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-4H-pyrrolo[3,2,1-ij]quinolin-4-one,obtained in example B1 (0.002 mol) in DMF (20 ml) for 1 hour. Zn(CN)₂(0.0031 mol) then Pd(PPh₃)₄ (0.002 mol) were added. The mixture wasstirred at 80° C. for 4 hours, cooled, poured out into ice water,filtered over celite and extracted with DCM. The organic layer wasseparated, dried (MgSO₄), filtered, and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (15-35μm)(eluent: CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.1 to 94/6/0.2). The pure fractionswere collected and the solvent was evaporated, yielding 0.41 g (41%) of4-[[6-(3-chlorophenyl)-1,2-dihydro-4-oxo-4H-pyrrolo[3,2,1-ij]quinolin-8-yl](4-methyl-4H-1,2,4-triazol-3-yl)methyl]-benzonitrile, melting point 174° C. (compound 2).

EXAMPLE B3

Nitric acid (2 ml) was added at 0° C. to a solution of sodium nitrite(0.0014 mol) in water (2 ml). The mixture was stirred for 5 minutes. Asolution of (intermediate 7) (0.0012 mol) in THF (8 ml) was addeddropwise. The mixture was stirred at 0° C. for 1 hour, poured out intoK₂CO₃ 10% and extracted with EtOAc. The organic layer was separated,dried (MgSO₄), filtered, and the solvent was evaporated. The residue(1.1 g) was purified by column chromatography over silica gel (15-40 μm)(eluent: CH₂Cl₂/CH₃OH/NH₄OH 94/6/0.2). The pure fractions were collectedand the solvent was evaporated. The residue (0.52 g) was crystallizedfrom acetonitrile. The precipitate was filtered off and dried; yielding0.22 g (33%) of7-(3-chlorophenyl)-9-[(4-chlorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-2,3-dihydro-1H,5H-benzo[ij]quinolizin-5-one,melting point 183° C. (compound 3).

EXAMPLE B4

Sulfuric acid concentrated (2 drops) was added to a solution of compound46-(3-chlorophenyl)-8-[(4-fluorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(which was made in a similar way as described in example B1) (0.0001mol) in acetonitrile (1 ml). The mixture was stirred and refluxedovernight. Water and NH₄OH were added. The mixture was extracted withDCM. The organic layer was separated, dried (MgSO₄), filtered, and thesolvent was evaporated. The residue (0.056 g) was taken up in DCM. Theprecipitate was filtered, washed with diethyl ether and dried; yielding0.054 g (100%) ofN-[[6-(3-chlorophenyl)-1,2-dihydro-4-oxo-4H-pyrrolo[3,2,1-ij]quinolin-8-yl](4-fluorophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-acetamide,melting point 196° C. (compound 5).

EXAMPLE B5

Sulfuric acid concentrated (0.3 ml) was added to a mixture of compound 3(0.0005 mol) in methanol (6 ml). The mixture was stirred and refluxedfor 72 hours, poured out into ice water, basified with NH₄OH andextracted with DCM. The organic layer was separated, dried (MgSO₄),filtered, and the solvent was evaporated. The residue (0.268 g) waspurified by column chromatography over silica gel (10 μm) (eluent:CH₂Cl₂/CH₃OH 98/2). The pure fractions were collected and the solventwas evaporated, yielding 0.05 g (17%) of7-(3-chlorophenyl)-9-[(4-chlorophenyl)methoxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-2,3-dihydro-1H,5H-benzo[ij]quinolizin-5-one,melting point 132° C. (compound 6).

EXAMPLE B6

Sulfuric acid concentrated (2 drops) was added to a mixture of compound4 (which was made in a similar way as described in example B1) (0.0002mol) in 1,2-ethanediol (1 ml). The mixture was stirred at 125° C.overnight. Water and ice were added. NH₄OH (1 drop) was added. Theprecipitate was filtered, washed with diethyl ether and dried. Theresidue (0.118 g) was purified by column chromatography over silica gel(10 μm)(eluent: toluene/iPrOH/NH₄OH 70/29/1). The pure fractions werecollected and the solvent was evaporated, yielding 0.058 g (53%) of6-(3-chlorophenyl)-8-[(4-fluorophenyl)(2-hydroxyethoxy)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one,melting point 138° C. (compound 7).

EXAMPLE B7

A mixture of compound 4 (which was made in a similar way as described inexample B1) (0.0002 mol) in 1,3-dimethyl-2-imidazolidinone (0.6 ml) wasstirred at room temperature for 10 minutes. Thionyl chloride (0.0008mol) was added dropwise at room temperature. The mixture was stirred atroom temperature for 3 hours and 30 minutes. 4H-imidazole (0.004 mol)was added portionwise. The mixture was stirred at room temperatureovernight, poured out into ice water. The precipitate was filtered offand dried, yielding 0.033 g of6-(3-chlorophenyl)-8-[(4-fluorophenyl)-1H-imidazol-1-yl(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1,2-dibydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(compound 8).

EXAMPLE B8

A mixture of compound 4 (which was made in a similar way as described inexample B1) (0.0002 mol) in 1,3-dimethyl-2-imidazolidinone (0.6 ml) wasstirred for 10 minutes. Thionyl chloride (0.0008 mol) was added dropwiseat room temperature. The mixture was stirred at room temperature for 3hours and 30 minutes then added dropwise at 5° C. to NH₃/CH₃OH 7N (0.004mol). The mixture was stirred at room temperature overnight, poured outinto ice water and extracted with DCM. The organic layer was separated,dried (MgSO₄), filtered, and the solvent was evaporated. Water wasadded. The mixture was stirred at room temperature for 1 hour. Theprecipitate was filtered, washed with diethyl ether and dried. Theresidue (0.048 g) was taken up in diethyl ether. The precipitate wasfiltered off and dried. Diethyl ether was added. The mixture wasevaporated, yielding 0.034 g of8-[amino(4-fluorophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-6-(3-chlorophenyl)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(compound 9).

EXAMPLE B9

Benzyltriethylammonium chloride (0.0003 mol) then iodomethane (0.0006mol) was added to a solution of compound 4 (which was made in a similarway as described in example B1) (0.0004 mol) in THF (2 ml) and NaOH 3N(2 ml). The mixture was stirred at room temperature for 3 days. Waterwas added. The mixture was extracted with EtOAc. The organic layer wasseparated, dried (MgSO₄), filtered, and the solvent was evaporated. Theresidue (0.217 g ) was purified by column chromatography over silica gel(eluent: DCM/evaporated. 10 μm). The pure fractions were collected andthe solvent was evaporated. The residue (0.08 g) was crystallized from2-propanone/DIPE. The precipitate was filtered off and dried. Thefiltrate was evaporated, yielding 0.04 g (20%) of6-(3-chlorophenyl)-8-[(4-fluorophenyl)methoxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(compound 10).

Table F-1 and F-2 lists the compounds that were prepared according toone of the above Examples. The following abbreviations were used in thetables: Co. No. stands for Compound Number, Ex. [Xn°] referred to thesame method as described in the Xn° example. TABLE F-1 intermediates

Table F2 Final Compounds

C. PHARMACOLOGICAL EXAMPLE EXAMPLE C.1 “In Vitro Asay for Inhibition ofFarnesyl Protein Transferase”

An in vitro assay for inhibition of farnesyl transferase was performedessentially as described in WO 98/40383, pages 33-34. When appropriate,IC₅₀-values (concentration of the drug, needed to reduce the product ofthe enzymatic reaction, to 50% of the conrol) were computed using probitanalysis for graded data (Finney, D. J., Probit Analuses, 2^(nd) Ed.Chapter 10, Graded Responses, Cambridge Univerity Press, Cambridge1962). Herein (see table F-3) the effects of test compounds areexpressed as pIC₅₀ (the negative log value of the IC₅₀-value). Also theintermediate compounds described in the table F-1 show activity in thein vitro assay for inhibition of farnesyl protein transferase.

EXAMPLE C.2 “Ras-Transformed Cell Phenotype Reversion Assay”

The ras-transformed cell phenotype reversion assay was performedessentially as described in WO 98/40383, pages 34-36.

EXAMPLE C.3 “Farnesyl Protein Transferase Inhibitor Secondary TumourModel”

The farnesyl protein transferase inhibitor secondary tumour model wasused as described in WO 98/40383, page 37. TABLE F-3 Enzyme activity Co.No. pIC50 1 7.669 2 8.695 3 8.087 4 8.239 11 >7 12 <7 13 8.232 5 8.4696 >7 7 8.403 8 8.416 9 8.526 10 7.533

D. COMPOSITION EXAMPLE Film-Coated Tablets

Preparation of Tablet Core

A mixture of 100 g of a compound of formula (I), 570 g lactose and 200 gstarch is mixed well and thereafter humidified with a solution of 5 gsodium dodecyl sulfate and 10 g polyvinyl-pyrrolidone in about 200 ml ofwater. The wet powder mixture is sieved, dried and sieved again. Thenthere is added 100 g microcrystalline cellulose and 15 g hydrogenatedvegetable oil. The whole is mixed well and compressed into tablets,giving 10.000 tablets, each comprising 10 mg of a compound of formula(I).

Coating

To a solution of 10 g methyl cellulose in 75 ml of denaturated ethanolthere is added a solution of 5 g of ethyl cellulose in 150 ml ofdichloromethane. Then there are added 75 ml of dichloromethane and 2.5ml 1,2,3-propanetriol 10 g of polyethylene glycol is molten anddissolved in 75 ml of dichloromethane. The latter solution is added tothe former and then there are added 2.5 g of magnesium octadecanoate, 5g of polyvinyl-pyrrolidone and 30 ml of concentrated colour suspensionand the whole is homogenated. The tablet cores are coated with the thusobtained mixture in a coating apparatus.

1. A compound of formula (I):

or a pharmaceutically acceptable salt or N-oxide or stereochemicallyisomeric form thereof, wherein r and s are each independently 1, 2 or 3;X is oxygen or sulfur; -A- is a bivalent radical of formula selectedfrom the group consisting of—CH═CH—  (a-1)—CH₂—CH₂—  (a-2)—CH₂—CH₂—CH₂—  (a-3)—CH₂—O—  (a-4) and—CH₂—CH₂—O—  (a-5) wherein optionally one hydrogen atom may be replacedby C₁₋₄alkyl; >Y¹—Y²— is a trivalent radical of formula>C═CR5—  (y-1) or>CH—CHR⁵—  (y-2) wherein R⁵ is hydrogen, halo, or C₁₋₆alkyl; R¹ isselected from the group consisting of hydrogen, hydroxy, halo, cyano,nitro, C₁₋₆alkyl, —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl,cyanoC₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, trihalomethyl,-C₁₋₆alkyl-NR⁴¹R¹⁵, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, trihalomethoxy,C₂₋₆alkenyl, C₂₋₆alkynyl, —CHO, C₁₋₆alkylcarbonyl, hydroxycarbonyl,C₁₋₆alkyloxycarbonyl, —CONR¹⁴R¹⁵, —CONR¹⁴—O—C₁₋₆alkyl,—CONR¹⁴-C₁₋₆alkenyl, —OC(O)R¹⁶, —CR¹⁶═NR¹⁷ and of —CR¹⁶═N—OR¹⁷; p is 0,1 or 2; R¹² and R¹³ are independently hydrogen or C₁₋₆ alkyl and areindependently defined for each iteration of p in excess of 1; R¹⁴ andR¹⁵ are independently hydrogen, C₁₋₆ alkyl or—(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl; two R¹ substituents adjacent to oneanother on the phenyl ring may form together a bivalent radical offormula selected from the group consisting of—O—CH₂—O—  (b-1)—O—CH₂—CH₂—O—  (b-2)—O—CH═CH—  (b-3) and—O—CH₂—CH₂  (b-4); R¹⁶ and R¹⁷are independently selected from the groupconsisting of hydrogen, C₁₋₆ alkyl and —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl;R² is selected from the group consisting of hydrogen, hydroxy, halo,cyano, nitro, C₁₋₆alkyl, C₁₋₆alkyloxy, trihalomethyl, C₁₋₆alkylthio,di(C₁₋₆alkyl)amino, -C₁₋₆alkyl-NR¹⁴R¹⁵, trihalomethoxy, C₂₋₆alkenyl,hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR¹⁴R¹⁵,—(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl, cyanoC₁₋₆alkyl, mono- ordi-haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,R¹⁶SC₁₋₆alkyl, Het¹C₁₋₆alkyl, Het¹C₁₋₆alkyl in which the C₁₋₆alkylmoiety is substituted by hydroxy, Het¹SC₁₋₆ alkyl,-C₁₋₆alkylNR¹⁴-C₁₋₆alkyloxyC₁₋₆alkyl, -C₁₋₆ alkylNR¹⁴C₂₋₆alkenyl,-C₁₋₆alkylNR¹⁴C₂₋₆alkynyl, -C₁₋₆alkylNR¹⁴C₁₋₆alkyl-NR¹⁴R¹⁵,-C₁₋₆alkylNR¹⁴C₁₋₆alkyl-Het¹, -C₁₋₆alkylNR¹⁴C₁₋₆alkylC(O)OC₁₋₆alkyl,C₂₋₆alkynyl, —CHO, C₁₋₆alkylcarbonyl, —CONR¹⁴-C₁₋₆alkyl-NR¹⁴R¹⁵,—CONR¹⁴—O-C₁₋₆alkyl, —CONR¹⁴-C₁₋₆alkenyl, —NR¹⁴R¹⁵, —OC(O)R¹⁶,—CR¹⁶═NR¹⁷, —CR¹⁶═N—OR¹⁷ and —C(NR¹⁸R¹⁹)═NR²⁰; two R² substituentsadjacent to one another on the phenyl ring may together form a bivalentradical of formula selected from the group consisting of—O—CH₂—O—  (b-1),—O—CH₂'CH₂—O—  (b-2)—O—CH═CH—  (b-3)—O—CH₂—CH₂—  (b-4) and—CH₂—O—CH₂  (b-5); R¹⁶ and R¹⁷ are independently selected from the groupconsisting of hydrogen, C₁₋₆ alkyl and —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl;R¹⁸, R¹⁹ and R²⁰ are independently hydrogen and C₁₋₆alkyl; R³ isselected from the group consisting of hydrogen, halo, C₁₋₆alkyl,—(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl, haloC₁₋₆alkyl, cyanoC₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, hydroxycarbonylC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, -C₁₋₆alkyl-NR¹⁴R¹⁵, -C₁₋₆alkyl-CONR¹⁴R¹⁵,Het¹, and a radical of a formula selected from the group consisting of—O—R⁶  (c-1)—NR⁷R⁸  (c-2) or—N═CR⁶R⁷  (c-3) wherein R⁶ is selected from the group consisting ofhydrogen, C₁₋₆alkyl, —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl, a group of formula—NR¹⁴R¹⁵ or -C₁₋₆alkylC(O)OC₁₋₆alkyl NR¹⁴R¹⁵, or a radical of formula-Alk-OR⁹ and -Alk-NR¹⁰R¹¹; R⁷ is selected from the group consisting ofhydrogen, C₁₋₆alkyl, and —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl; R⁸ is selectedfrom the group consisting of hydrogen, hydroxy, C₁₋₆alkyl,—(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl, C₁₋₆alkylcarbonylamino,C₁₋₆alkylcarbonyl, haloC₁₋₆alkylcarbonyl, Ar¹C₁₋₆alkylcarbonyl,Het¹C₁₋₆alkylcarbonyl, Ar¹carbonyl, C₁₋₆alkyloxycarbonyl,trihaloC₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxyC₁₋₆alkylcarbonyl,aminocarbonyl, mono- or di(C₁₋₆alkyl)aminocarbonyl wherein the alkylmoiety may optionally be substituted by one or more substituentsindependently selected from Ar¹ and C₁₋₆alkyloxycarbonyl substituents,aminocarbonylcarbonyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, ora radical of formula -Alk-OR⁹ or Alk-NR¹⁰R¹¹, wherein Alk isC₁₋₆alkanediyl; R⁹ is selected from the group consisting of hydrogen,C₁₋₆alkyl, and —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl; R¹⁰ is selected from thegroup consisting of hydrogen,C₁₋₆alkyl, and—(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl; R¹¹ is selected from the groupconsisting of hydrogen, C₁₋₆alkyl, and —(CR¹²R¹³)_(p)-C₃₋₁₀cycloalkyl;R⁴ is hydrogen or C₁₋₆alkyl; Ar¹ is independently selected from thegroup consisting of phenyl, naphthyl and phenyl or naphthyl substitutedby one to five substituents each independently selected from the groupconsisting of halo, hydroxy, cyano, nitro, amino, C₁₋₆alkyl,haloC₁₋₆alkyl, -alkylNR¹⁴R¹⁵, C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl,C₁₋₆alkyloxycarbonyl, aryloxy, —NR¹⁴R¹⁵, C₁₋₆alkylsulfonylamino, oximeor phenyl, or a bivalent substituent of formula —O—CH₂—O— and—O—CH₂—CH₂—O—; Het¹ is a mono- or bi-cyclic heterocyclic ring containingone or more heteroatoms selected from the group consisting of oxygen,sulphur and nitrogen and optionally substituted by one or twosubstituents each independently selected from the group consisting ofhalo, hydroxy, cyano, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, -alkylNR¹⁴R¹⁵,C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR¹⁴R¹⁵,—NR¹⁴R¹⁵, C₁₋₆alkylsulfonylamino, oxime or phenyl; aryl is independentlyselected from the group consisting of phenyl, naphthalenyl, phenylsubstituted with one or more substituents each independently selectedfrom the group consisting of halo, C₁₋₆alkyl, C₁₋₆alkyloxy,trifluoromethyl, cyano, and hydroxycarbonyl; or naphtalenyl substitutedwith one or more substituents each independently selected from the groupconsisting of halo, C₁₋₆alkyl, C₁₋₆alkyloxy, trifluoromethyl, cyano andhydroxycarbonyl.
 2. A compound according to claim 1 in which r and s areeach independently 1; X is oxygen; -A- is a bivalent radical of aformula selected from the group consisting of (a-2), (a-3) and (a-4);>Y¹—Y²— is a trivalent radical of formula (y-1) wherein R⁵ is hydrogenor halo; R¹ is halo; R² is halo or cyano; R³ is selected from the groupconsisting of hydrogen, hydroxy, amino, C₁₋₆alkyloxy,hydroxyC₁₋₆alkyloxy, C₁₋₆alkylcarbonylamino and N-imidazolyl; and R⁴ isC₁₋₂alkyl.
 3. A compound according to claim 1 selected from the groupconsisting of:6-(3-chlorophenyl)-1,2-dihydro-8-[(4-iodophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-4H-pyrrolo[3,2,1-y]quinolin-4-one;4-[[6-(3-chlorophenyl)-1,2-dihydro-4-oxo-4H-pyrrolo[3,2,1-i]quinolin-8-yl](4-methyl-4H-1,2,4-triazol-3-yl)methyl]-benzonitrile;7-(3-chlorophenyl)-9-[(4-chlorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-2,3-dihydro-1H,5H-benzo[y]quinolizin-5-one;6-(3-chlorophenyl)-8-[(4-fluorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one;6-(4-chlorophenyl)-8-[(4-chlorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-yi]quinolin-4-one;6-(3-bromophenyl)-8-[(4-bromophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-i]quinolin-4-one;N-[[6-(3-chlorophenyl)-1,2-dihydro-4-oxo-4H-pyrrolo[3,2,1-ij]quinolin-8-yl](4-fluorophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-acetamide;7-(3-chlorophenyl)-9-[(4-chlorophenyl)methoxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-2,3-dihydro-1H,5H-benzo[ij]quinolizin-5-one;6-(3-chlorophenyl)-8-[(4-fluorophenyl)(2-hydroxyethoxy)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one;6-(3-chlorophenyl)-8-[(4-fluorophenyl)-1H-imidazol-1-yl(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-4H-pyrrolo[3,2,1-i]quinolin-4-one;8-[amino(4-fluorophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-6-(3-chlorophenyl)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-oneand a pharmaceutically acceptable salts thereof.
 4. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier, and asactive ingredient a therapeutically effective amount of a compound asdescribed in claim
 1. 5. A process for preparing a pharmaceuticalcomposition as claimed in claim 4 wherein a therapeutically effectiveamount of a compound as claimed in claim 1 is intimately mixed with apharmaceutically acceptable carrier.
 6. A compound according to claim 1for use as a medicine.
 7. The use of a compound according to claim 1 inthe manufacture of a medicament for inhibiting tumour growth.
 8. The useof a compound according to claim 1 in the manufacture of a medicament totreat proliferative disorders.
 9. A process for the preparation of acompound as claimed in claim 1 which comprises: a) removing the —S—R²¹group from the intermediate of formulae (IVa) wherein R⁴ is C₁₋₆alkyl,R³ is hydroxy and R²¹ is hydrogen or C₁₋₆ alkyl with the formation of acompound of formula (I-a) wherein R⁴ is C₁₋₆alkyl and R³ is hydroxy; and

b) reacting an intermediate ketone of formula (II) with an intermediatetriazole reagent of formula (III-b) wherein P is an optional protectivegroup and subsequently removal of P with the formation of a compound offormula (I-b) wherein R⁴ is hydrogen and R³ is hydroxy; and

c) optionally effecting one or more of the following conversions in anydesired order: (i) converting a compound of formula (I) into a differentcompound of formula (I); (ii) converting a compound of formula (I) in toa pharmaceutically acceptable salt or N-oxide thereof; (iii) convertinga pharmaceutically acceptable salt or N-oxide of a compound of formula(I) into the parent compound of formula (I); (iv) preparing astereochemical isomeric form of a compound of formula (I) or apharmaceutically acceptable salt or N-oxide thereof.
 10. An intermediateof formula (IFa) wherein R¹ and R² are as defined in claim 1 and whereinR³ is hydroxy, R⁴ is C₁₋₆alkyl, and R²¹ is hydrogen or C₁₋₆alkyl;